Friday, 30 November 2012

The slides from my talk in Marbella; you can download them from my slideshare site!

"The main messages in the talk are:1. We must adopt treatment practices from oncology (NEDD) and rheumatology (TTT) to render MSers DAF (disease-activity free). 2. We need to formulate a definition of what a cure in MS will look like and work towards this aim.3. We must not assume that anti-inflammatory therapies don't work in progressive MS; we may slow down the rate of progression. This is what happens with mitoxantrone.4. Treat as early as possible; delaying treatment has long-term consequences for MSers, for example increased mortality.5. Despite what the critics say 1st-line treatments do have an impact on long-term outcomes, albeit it moderate.6. You can't compare MSers who are on treatment with MSers who are not on treatment; selection bias makes it impossible. MSers on treatment are more likely to have active disease and less likely to have benign disease. In comparison, those not on treatment are more likely to have benign disease and less likely to have active disease; the latter is why they elected not to go onto DMTs in the first place.7. We don't put MSers on treatment and leave them on treatment; we now monitor for response or non-response and switch; sideways between classes or escalate to more efficacious drugs depending on the level of disease activity.8. Non-response to DMTs is monitored using clinical (relapses & disease progression), MRI (new and enlarging T2 lesions and Gd-enhancing lesions) and with biomarkers (neutralising antibodies). 9. Clinical and MRI activity on interferon-beta, and by inference glatiramer acetate, does not mean the same as activity in natural history studies off DMTs (slide 23 & 25). In natural history studies relapses don't predict disease progression, except in the first 2 years after disease onset. In comparison relapses on DMTs are a harbinger of progression. Therefore if you are on interferon-beta and glatiramer acetate and are having ongoing relapses and MRI activity you should discuss with your neurologist about switching treatment.10. Disease progression be gets disease progression.11. Confirmed disease progression in clinical trials is typically driven by relapses. I personally ignore disease progression data that is not matched by a meaningful change in the mean or median EDSS scores across the study. This is an artefact of how we use survival analysis on the EDSS. To illustrate this point I compare data from interferon-beta-1b and alemtuzumab trials.

12. The new target in MS treatment is disease-activity-free status, i.e. treat-to-target (TTT) or treat so that there is no evidence of detectable disease activity (NEDDA).13. Whilst we wait for long-term data to come in from the alemtuzumab extension study let MSers have the option of going onto treatment in the hope that their disease will flat-line, i.e. remain disease activity free for a long period of time possibly permanently (cure). They also need to know this is an experiment and that they may comeback with SPMS in 10 to 20 years time. In the interim we need to develop treatments that delay or prevent the post-autoimmune inflammatory neurodegeneration that occurs in MS; in short neuroprotective treatments. This is why we need MSers to volunteer for neuroprotection studies. 14. Who should decide on early aggressive treatment and what risks are they willing to take? 15. Unfortunately, the decision regarding aggressive early treatment may ultimately be made by regulators who license these treatments or the payers who pay for these treatments. If the regulators think they are too aggressive they will be given a 2nd or 3rd license with a very narrow indication. In other words only a small number of MSers will be eligible for treatment If they are too expensive then the payers may restrict access to these drugs; it is clear that we are entering a price sensitive era of drug accessibility."CoI: multiple (slide 2)

BACKGROUND: The
mechanisms of multiple sclerosis (MS) pathogenesis are still largely
unknown. The heterogeneity of disease manifestations make the prediction
of prognosis and choice of appropriate treatment protocols challenging.
Recently, increased cerebrospinal fluid (CSF) levels of the B-cell
chemokine CXCL13 was proposed as a possible marker for a more severe
disease course and conversion from clinically isolated syndrome (CIS) to
relapsing-remitting MS (RRMS).

OBJECTIVE: To
investigate whether there are genetic susceptibility variants in MS
that correlate with the levels of CXCL13 present in the CSF of MS
patients.

METHODS: We
genotyped the human leukocyte antigens HLA-DRB1 and HLA-A, plus a panel
of single nucleotide polymorphisms (SNPs) that have been associated
with susceptibility to MS and then correlated the genotypes with the
levels of CXCL13, as measured with ELISA in the CSF of a total of 663
patients with MS, CIS, other neurological diseases (OND) or OND with an
inflammatory component (iOND).

CONCLUSION: Our
results pointed towards a genetic predisposition for increased CXCL13
levels, which in MS patients correlates with the severity of the disease
course.

CXCL13 is a small cytokine belonging to the CXC chemokine family. As its name suggests, this chemokine is selectively chemotactic for B cells and elicits its effects by interacting with chemokine receptorCXCR5.CXCL13 and its receptor CXCR5 control the organization of B cells within follicles of lymphoid tissues.
One hypothesis about the course of MS is that severity depends on B
cell follicles. The chemokine CXCL13 has been implicated in
this. In this study the authors examine if they could find clusters of
MS susceptibility genes that are associated with more CXCL13. They found
a cluster of 5 genes, which are linked to control of inflammation. This study will need to be replicated.

Is there an alternative to Big Pharma for developing new drugs for MS?

With the current level of risk associated with drug development and the level of regulatory red-tape it seems unlikely. Even Big Pharma themselves are having second thoughts about the current paradigm and trying new things. Many companies have closed down their neuroscience research centres in Europe and are partnering with academic institutions to reduce the costs of preclinical drug development. Ten of the world’s biggest drug makers have launched Transcelerate Biopharma to reduce costs associated with the complexity of drug development. Transcelerate Biopharma is focusing on areas where clinical drug development is wasteful and duplicates procedures like training clinicians, running websites or data portals, or creating procedures to document the benefits and side effects of new medicines. Interestingly, Transcelerate Biopharma will be a non-profit. The ten companies that are supporting it are:

Abbott

AstraZeneca

Boehringer-Ingelheim

Bristol-Myers Squibb

Eli Lilly and Company

GlaxoSmithKline

Johnson & Johnson

Pfizer

Genentech-Roche

Sanofi

The aims of Transcelerate Biopharma are admirable, but they still underpin BigPharmas' main aim of launching novel drugs that are big earners. The problem we are having in academia is the repurposing of drugs, or developing drugs that BigPharma have discarded. Take Simvastatin for example; how is Dr Chataway and his colleagues, who have a positive phase 2 neuroprotective study, going to take this forward when Simvastatin is off patent? Merck-Serono stopped the development of oral cladribine for MS, despite it already being licensed in Russia and Australia. Can we, the MS community resuscitate cladribine? The cladribine results are very good and in my opinion would make a big difference to the treatment of RRMS and potentially progressive MS. How do we get cladribine back on the table?

We need an alternative system to one BigPharma uses. Regulators and politicians need to acknowledge this; in particular in this age of austerity when drug budgets are soaring. The current pharma model is broken and the costs associated with it are too high to be sustainable in the long-term. I have been asking you the readers of this blog, in particular those who are always bashing BigPharma, for alternatives for over 2 years. Some of you have suggested a new Tax or levy on BigPharma drugs to pay for non-profit drug development. This is unlikely to work if the regulatory red-tape remains so complex and expensive. In addition, the skill set resides in industry. Taxation as a way of paying for new initiatives seldom works; it is inefficient. Personally, I would prefer a market-driven system.

As a start we need to get regulators and politicians to lower the bar for non-profit or academic drug development. They should create incentives in a similar way they have done for orphan drug development. For example, allow the design of adaptive phase 3 efficacy programmes to be done at the same time the drug is given a provisional license. This will allow the necessary data to be collected at the same time the drug is being marketed under controlled conditions. For example, the EMA and FDA have concerns about the long-term safety of oral cladribine. Why not give the drug a provisional license and allow the drug to be sold on condition that every MSer who goes on the drug is registered in a well-controlled pharmacovigilance study to assess the risk of the drug. This study would need a control group to compare the relative risks; the control group could be subjects going onto interferon-beta or glatiramer acetate. Instead the EMA and FDA have thrown the baby out with the bathwater and MSers are being denied a potentially very effective drug. We need to change this!

I therefore propose starting a new organisation to lobby our politicians to change the paradigm and create an alternative to BigPharma to develop drugs for MS. The working model will be a non-profit, or social entrepreneurship, with the aim of getting legislation enacted similar to that for orphan-diseases; the primary objective to aid academic and non-profit drug development. The aim is to get drugs - which are off-patent or don’t have the necessary IP life-span for BigPharma to recoup development costs and make a profit - to market at an earlier stage under a provisional license, whilst the data is being collected for a definitive or full license.

This organisation needs a name, seed money and help from politicians or stakeholders. If you want to be part of this initiative please register your interest below and any suggestions you may have to help. The organisation will need a leader, administrators, secretaries, etc. Volunteers are most welcome.

Blood-brain barrier disruption, microglial activation and
neurodegeneration are hallmarks of multiple sclerosis. However, the
initial triggers that activate innate immune responses and their role in
axonal damage remain unknown. Here we show that the blood protein
fibrinogen induces rapid microglial responses toward the vasculature and
is required for axonal damage in neuroinflammation. Using in vivo
two-photon microscopy, we demonstrate that microglia form perivascular
clusters before myelin loss or paralysis onset and that, of the plasma
proteins, fibrinogen specifically induces rapid and sustained microglial
responses in vivo. Fibrinogen leakage correlates with areas of
axonal damage and induces reactive oxygen species release in microglia.
Blocking fibrin formation with anticoagulant treatment or genetically
eliminating the fibrinogen binding motif recognized by the microglial
integrin receptor CD11b/CD18
inhibits perivascular microglial clustering and axonal damage. Thus,
early and progressive perivascular microglial clustering triggered by
fibrinogen leakage upon blood-brain barrier disruption contributes to
axonal damage in neuroinflammatory disease.

We have known for some time that production of elements of the blood clotting system, such as fibrin and fibrinogen are deposited in lesions of MS and EAE. It was also shown many years agoI mean many years ago, that this occurs before much infiltration occurs.

Green = fibrinogen around blood vessels, red = white blood cells
This data is from experiments done many years ago

We recently talked about two photon microscopy and imaging in the living animal and this has been used in this current study. This suggests that leakage of blood proteins into the brain tissue can activate microglial cells to cluster as a early stage in lesion formation. This can be seen below with leakage of dextran (red) from the blood vessels into brain tissue and the clustering of microglia (green)

It was shown that if you block fibrin deposition that this can influence lesion formation, it was shown many years ago thatmanipulating this fibrinogen productioncan influence the disease. in EAE. This inhibited clusters, however if I killed of T cells it would no doubt inhibit clusters as disease would not start. The authors then suggest that fibrinogen is part of the nerve destructive process, because if they deplete fibrinogen they get less nerve damage, however as they get less lesion formation surely it is obvious that this would happen. Anyway, it is then shown that when fibrinogen activates the microglia they can produce reactive oxygen species, which can be damaging to nerves. So we seem to be agreed that macrophages/microglia can be the bad guys in generating damage. The will also be the good guys later-on clearing the damage up.

Holes in Blood vessels as depicted above do not happen, but junctions are remodelled

What drives these lesions....I would say T cell derived cytokines then macrophages, microglia do the damage. In previous vidoes we have seen T cells associated with damage also.

Are these microglial clusters the same as pre-active lesions in MS, I am not sure they are as I believe pre-active lesions do not all centre on blood vessels, but stressed oligodendrocytes. With this approach any insult that releases fibrinogen would result in the same lesion, so Stroke etc, would look like MS. So there are many components that need to be layered into this view but watching events occuring in real time is revolutionising how we see events.

Check out the Movies and also look at the reference list (e.g. 11-13 in paper) and check out the movies in previous papers, they really are spectacular.

Fatigue
is reported as the most common symptom by patients with multiple
sclerosis (MS). The physiological and functional parameters related to
fatigue in MS patients are currently not well established. A new
wearable wireless body measurement system, named Fatigue Monitoring
System (FAMOS), was developed to study fatigue in MS. It can
continuously measure electrocardiogram, body-skin temperature,
electromyogram and motions of feet. The goal of this study is to test
the ability of distinguishing fatigued MS patients from healthy subjects
by the use of FAMOS. This paper presents the realization of the
measurement system including the design of both hardware and dedicated
signal processing algorithms. Twenty-six participants including 17 MS
patients with fatigue and 9 sex- and age-matched healthy controls were
included in the study for continuous 24 h monitoring. The preliminary
results show significant differences between fatigued MS patients and
healthy controls. In conclusion, the FAMOS enables continuous data
acquisition and estimation of multiple physiological and functional
parameters. It provides a new, flexible and objective approach to study
fatigue in MS, which can distinguish between fatigued MS patients and
healthy controls. The usability and reliability of the FAMOS should
however be further improved and validated through larger clinical
trials.

Get the system improved so that it is an available tool to measure fatigue, which is very high on the list of problems with MS, but very under investigated. However, with tools to monitor are a step towards being able to treat. Part of the slowness in progress in MS is the lack of responsive outcomes.

#MSBlog: Hit hard and early!"I will be speaking at the European Charcot Foundation meeting in Marbella later this week (see programme below). I am talking in the session on "Time to change the treatment paradigm for people with MS?" I assume the question mark is asking whether or not the time for this is now or in the future.

My talk is on "Hit hard and Early", which is another way of saying early aggressive treatment. Although this symposium is sponsored by Genzyme they have had no input into arranging the meeting, or the symposium. I have been told it is an independent session. I am going to have to come up with some new material for this talk; my existing slide set is looking rather old and worn. I have therefore prepared a quick survey below to help; I plan to present the preliminary results at the meeting. I would therefore appreciate it if you could complete the survey if you feel comfortable doing it. Please leave any suggestions you may think will help me in making my case in the comments box. You help is much appreciated. Thank you!"

Wednesday, 28 November 2012

There has been some questions about the course of MS and whether the cause of relapsing MS and progressive MS are dependent or independent. Prof G is not sure if the two are dependent on each other, based on animal studies I would say they are probably independent mechanisms, but inter-related.

If you look at the age of onset of MS (Left graph-This is perhaps a bit loose as I am sure MS my start earlier before diagnosis), you can see it begins years earlier in RRMSers, who become SPMSers in over 60% of the time. This course tends to be higher in females than males. PPMSers tend to develop MS later in life (Left graph). You may be on the early end but there will be others on the late end of the spectrum.

If you look at the time to development of progressive MS it is on average the same if you are PPMS from onset or if you develop SPMS after RRMS (right graph). This sort of replicates a similar study by Confavreux in 2006, but the timing of the slopes are not quite the same. This is why some people say that progression is not dependent on relapses.

If progression does occur at a similar age, it suggests some issue with the aging process, such as failure to repair, that is central to the progression that occurs in both males and females, or there is some sub-clinical process that occurs in all MSers that takes time to show itself

Although some PPMSers are not happy that current drugs appear always directed to RRMS, at least on average PPMS rears its head later than in RRMS (left graph), so that progression starts at similar time, so that PPMSers have more of a disease-free time prior to diagnosis.

So you say relapses do not matter?. However, if you look to time to a disability point then it appears that if you have relapsing disease that you accumulate disability a few years faster, so inhibiting relapses is a good thing. Does progressive MS start much earlier and remain subclinical, whereas relapsing MS shows itself before going progressive?

In animals in EAE, progressive disability can occur after one attack or a few attacks and in our hands occurs faster in males than females, just as occurs in MS. In EAE the trigger is an inflammatory attack, in MS we can only speculate, but if you treat the immune response aggressively and early, the relapses stop and the onset of progression is limited. So in the era of the second generation DMT (the above data is not based on second generation DMT) we can only hope that it will slow the accumulation of disability and could it stop it. Nothing has discouraged me from that view yet.

In the largest sample studied to date, we measured cognitive functioning in children and adolescents with pediatric multiple sclerosis
(n = 187) as well as those with clinically isolated syndrome (n = 44).
Participants were consecutively enrolled from six United States
Pediatric Multiple Sclerosis
Centers of Excellence. Participants had a mean of 14.8 ± 2.6 years of
age and an average disease duration of 1.9 ± 2.2 years. A total of 65
(35%) children with multiple sclerosis
and 8 (18%) with clinically isolated syndrome met criteria for
cognitive impairment. The most frequent areas involved were fine motor
coordination (54%), visuomotor integration (50%), and speeded
information processing (35%). A diagnosis of multiple sclerosis
(odds ratio = 3.60, confidence interval = 1.07, 12.36, P = .04) and
overall neurologic disability (odds ratio = 1.47, confidence interval =
1.10, 2.10, P = .03) were the only independent predictors of cognitive
impairment. Cognitive impairment may occur early in these patients, and
prompt recognition is critical for their care.

Cognitive impairment can occur in all Msers and this also occurs in childhood MS and correlates with worse disability.

BACKGROUND: Age of onset of multiple sclerosis (MS) peaks in the 3rd and 4th decades and is rarely less than 18. Robust longitudinal studies in paediatric-onset MS (POMS) are limited, and a clearer understanding of outcome could optimise management strategies.

METHODS: Patients with disease onset <18 years were identified from a prospective population-based register. Clinical features including presenting symptoms, time to Expanded Disability Status Scale (EDSS) 4.0, 6.0 and 8.0 and onset of secondary progression were compared with patients with adult-onset MS (AOMS).

RESULTS: 111 POMS patients were identified from a cohort of 2068. No significant differences in sex ratio, familial recurrence, relapse rate, ethnicity or clinical symptoms at presentation were identified between POMS and AOMS. However, interval to second relapse was longer (5 vs 2.6 years, p=0.04) and primary progressive disease was less common (0.9% vs 8.5%, p=0.003) in POMS than in AOMS. POMS patients also took longer to develop secondary progressive disease (32 vs 18 years, p=0.0001) and to reach disability milestones (EDSS 4.0, 23.8 vs 15.5 years, p<0.0001; EDSS 6.0, 30.8 vs 20.4 years, p<0.0001; EDSS 8.0, 44.7 vs 39 years, p=0.02), but did so between 7.0 and 12 years younger than in AOMS.

CONCLUSIONS: 5.4% of patients with MS have POMS (2.7% <16 years; 0.3% <10 years) and have distinct phenotypic characteristics in early disease. Furthermore, while patients with POMS take longer to reach disability milestones, they do so at a younger age than their adult counterparts and could be considered to have a poorer prognosis. Management strategies for these patients should take account of these data.

The descriptions tell us the story, whilst young MSers appears to have more ability to tolerate the attacks and so it takes longer for progressive disease to develop. Alternatively could it be that RRMS shows itself in these children early but it takes longer for the neurodegenerative effects to show themselves, as such people who develop MS later in life, exhibit a higher incidence of progressive disease. As such cellular ageing senescence could be important in when neurodegeneration and progression kicks in.

#MSBlog: Steroids reduce the immune response to the JC virus that causes PML. Therefore steroids should only be used to treat not prevent IRIS.

#MSBlog: MSers with natalizumab-associated PML have a deficit in the cells that attack the JC virus.

"These two studies demonstrate that MSers with natalizumab-associated PML have a problem with the cells that attack the JC virus, the causes of PML. In addition, steroids that are often given to treat and/or prevent the inflammation that occurs when natalizumab is stopped or washed out blunts the cells ability to kill or destroy the cells infected with the virus. These studies provide some new insights into some of the immune function that is awry in MSers on natalizumab who develop PML. Can we use this information to test or furthe stratify the PML risk in individual MSers on Natalizumab? Maybe. Doing cellular tests like this are difficult to standardise. But they have been developed to help diagnose TB or tuberculosis. So may be we can do the same for PML?"

OBJECTIVE: To investigate the impact of corticosteroids (CS) on the viral-specific T-cell response, in particular the JC virus (JCV)-specific one, in an attempt to determine the optimal timing of CS in the management of progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome (PML-IRIS).

METHODS: A blood draw was performed before and 7 days after the administration of IV CS to 24 RRMSers. The phenotypic pattern of T cells was determined by CCR7 and CD45RA. To assess the impact of CS treatment on proliferative response of JCV-, influenza-, and Epstein-Barr virus (EBV)-specific T cells, a thymidine incorporation proliferation assay was performed. An intracellular cytokine staining assay was performed to determine the effect of CS treatment on the production of cytokine by virus-specific T cells. JCV T-cell assays were performed only in JCV-infected MSers as detected by serologies (Stratify) or detection of JCV DNA in the urine by PCR.

RESULTS: CS led T cells, CD4+ and CD8+, toward a less differentiated phenotype. There was a significant decrease of EBV-, influenza-, and JCV-specific T-cell proliferative response upon CS treatment. There was a significant decrease in the frequency of interferon (IFN) γ- and tumor necrosis factor (TNF) α-producing JCV-specific CD8+ T cells, but not EBV- or influenza-specific CD4+ or CD8+ T cells.

CONCLUSIONS: CS have a profound impact on the virus-specific T-cell response, especially on JCV, suggesting that when CS are considered, they should not be given before the onset of clinical or radiologic signs of IRIS. Studies addressing directly patients with MS with natalizumab-caused PML are warranted.

CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that methylprednisolone treatment decreases the frequency of JCV specific CD8+ T cells producing IFN-γ and TNFα, impairing control of JCV, suggesting this should be used to treat but not to prevent PML-IRIS. No clinical outcomes were measured.

Objectives: Here we characterize the JCV-specific T cell responses in healthy donors and natalizumab-treated MSers to reveal functional differences that may account for the development of natalizumab-associated PML.

Results: CD4 and CD8 T cell responses specific for all JCV proteins were readily identified in MSers and healthy volunteers. The magnitude and quality of responses to JCV and cytomegalovirus (CMV) did not change from baseline through several months of natalizumab therapy. However, the frequency of T cells producing IL-10 upon mitogenic stimulation transiently increased after the first dose. In addition, MSers with natalizumab-associated PML were distinguished from all other subjects in that they either had no detectable JCV-specific T cell response or had JCV-specific CD4 T cell responses uniquely dominated by IL-10 production. Additionally, IL-10 levels were higher in the CSF of individuals with recently diagnosed PML.

Conclusion: Thus, natalizumab-treated MSers with PML have absent or aberrant JCV-specific T cell responses compared with non-PML patients, and changes in T cell-mediated control of JCV replication may be a risk factor for developing PML. Our data suggest further approaches to improved monitoring, treatment and prevention of PML in natalizumab-treated MSers and other patients.

Tuesday, 27 November 2012

This is an Englishmetaphoricalidiom for an obvious truth that is either being ignored or going unaddressed. The idiomatic expression also applies to an obvious problem or risk no
one wants to discuss.

It is based on the idea that an elephant
in a room would be impossible to overlook; thus, people in the room who
pretend the elephant is not there have chosen to avoid dealing with the
looming big issue.

Prof G has used it in one context in the post below, it was presented to me in a few contexts at the weekend, I saw a Neuro use it to talk about Grey Matter lesions and the CCSVIers of course used it to lambast us.

"At the end of the 'Living with MS' meeting at the weekend MouseDoctor and I were fielding questions from MSers. One MSer chastised me for presenting new and up-coming clinical trials that all have, or will have, an upper cut-off age for recruitment. He was over 70.

He then accused me of being ageist. I apologised and said I don't make the rules. That is a bit of lie as I sit on committees that make some of the rules. The problem is that MS is viewed as a young persons disease and by the time MSers are over 60, or 70, they are at a stage of the disease that is confounded by age-related diseases, including natural ageing."

"I did mention to him the new European initiative to force Pharma companies to include elderly subjects in clinical trials. You may want to read the article that covers this issue. It is interesting that this issue also raises the problem of the "elephant in the room", i.e. the rapidly inflating costs of drug development. We all want cheap drugs! By forcing the Pharma industry to test drugs in children, and now elderly people, has knock on effects and will simply increase the price tag associated with new drugs further.

One of the biggest drivers of drug development costs are pre and post-marketing regulatory requirements. The generation of data to satisfy regulatory authorities and payers is simply driving-up costs and they are rapidly approaching a level that is unsustainable.

What should we do about this problem? I am not sure, but a sensible debate would be a starting point. At some stage we need to be pragmatic about drug development and focus on developing drugs for the age of austerity. There is little point developing drugs that half the world can't afford to use. Drugs for MSers are no exception!"

.... In almost every country, the proportion of people over 60 years of age is growing faster than any other age group, as a result of longer life expectancy and declining fertility rates. In Europe, the median age is already the highest in the world, ......

...... Although population aging is a mark of the success of public health policies, it also challenges the established way of implementing such policies. In the case of the European Medicines Agency (EMA), it has prompted an analysis of whether the regulatory system is adapted to taking the needs of older people into account in the development, approval, and use of medications.....

...... The process started in 2006, when the EMA provided an opinion on the adequacy of guidance on the elderly regarding medicinal products. In 2011, the agency's Committee for Human Medicinal Products adopted the EMA geriatric medicines strategy, marking its commitment to improving our understanding of how best to evaluate the benefit–risk ratio for a medication in older patients.....

...... First, the strategy recognizes that older people are the main users of medications — not a minority or special population (a fundamental difference between the geriatric and pediatric populations). Therefore, legislative and regulatory frameworks must be designed to ensure that the use of newly approved medicines in the intended population is supported by relevant data on the benefit–risk balance. The strategy's second aim is to improve the availability of information to patients and prescribers, to support safer use of medications.....

Objective: To investigate whether cognitive fatigue in MSers is a spontaneous phenomenon or whether it can be provoked or exacerbated through cognitive effort and motor exercise.

Methods: 32 MSers with cognitive fatigue according to the Fatigue Scale for Motor and Cognitive Functions (FSMC ≥ 22) performed attention tests (alertness, selective, and divided attention subtests from the TAP test battery for attention performance) twice during rest (baseline), and before and after treadmill training and cognitive load (a standardised battery of neuropsychological tests lasting 2.5 hours). Subjective exhaustion was assessed with a 10-point rating scale.

Results: Tonic alertness turned out to be the most sensitive test and showed significantly increased reaction times after treadmill training and after cognitive load. MSers' subjective assessment of exhaustion (10-point rating scale) and the objective test results were discrepant. In contrast, healthy control subjects (N = 20) did not show any decline of performance in the subtest alertness after cognitive or physical load.

Conclusion: Data favour the concept that fatigue is induced by physical and mental load. Discrepancies between subjective and objective assessment offer therapeutic options. The common notion of a purely "subjective" lack of physical and/or mental energy should be reconsidered.

"This is a poor study because it is very small and did not include inflammatory controls without central nervous system involvement. In other words could the findings be non-specific due to the effects of inflammation rather than MS? People with active rheumatoid arthritis and other inflammatory syndromes also suffer from significant fatigue.How can we help MSers with fatigue?"

"Step 1: make sure you have good sleep hygiene and are not taking medication that is sedating. Sleep hygiene could be improved by avoiding stimulants or alcohol and not sleeping in the day; treating pain, spasms, restless legs, bladder dysfunction, anxiety and depression. All of these can affect sleep."

"Step 2: treating your energy levels as being a finite resource that need to rationed; i.e. plan your day and your activities so that you don't do too many tiring things in one day."

"Step 3: if you are deconditioned or unfit start a graded aerobic exercise programme; it is counter intuitive but exercise improves energy levels. I usually advise you do this through a physiotherapist."

"Step 4: enrol yourself on a behavioural therapy programme. This typically teaches your ways of changing your life to cope and deal with your fatigue."

"Step 5: speak to your neurologist. He/she may be able to prescribe medications that can help for fatigue. Don't hold your breath there are no licensed therapies for MS-related fatigue. We use drugs off-license with moderate effect and results. The most commonly prescribed drugs are amantadine and modafanil!"

"Please don't forget that fatigue is a normal physiological phenomenon. So it is normal to get tired! Ask me I feel tired most of the time; generation-F! F for fatigue!"

Monday, 26 November 2012

"The headline result is that MSers rate a delay in disease progression the most important outcome measures in relation to DMTs.""The problem with disability progression in relatively short RRMS clinical trials is that the outcome measure is driven by relapses. Relapses change the EDSS in the short-term, which may not relate to long-term disability progression; I have said, on may occasions in the recent past, that the correlation between relapses and long-term outcome is very poor."

"How do relapses drive short-term disability progression? This occurs because of the way we analyse disability progression using a statistical technique called the survival curve. For example, if you have an EDSS of 2.0 and have a relapse that increases your EDSS to 4.0, and your EDSS stays at this level for 4 months before you recover over the next 6 months back to an EDSS of 2.0, you will defined in the trial as having progressed, simply because your EDSS increased by more than 1.0 point for longer than 3 months. Despite having no effect on the average EDSS scores across a population of MSers in clinical trials many DMTs claim to have an impact on disability progression simply because of this effect; this scenario happens because more relapses occur in trial subjects on placebo than on active treatment.""This effect of relapses on the survival curve is a major confounder and is the reason why I believe that to claim that a particular drug has impact on disability progression it also need to impact on the average EDSS scores across the study and have an impact on objective MRI measures that we have linked to disease progression, for example brain atrophy. I am therefore very impressed that 38% of readers of this blog rated brain atrophy as the most important outcome measure for a DMT. I am not sure in myself that it should be rated this highly at this point in time, simply because we still have a lot for us to learn about its meaning and role in MS. Despite this brain atrophy does offer us a window into the brain and probably correlates with neuroprotective effects of DMTs. This is why DMTs that have a positive impact on brain atrophy are more-than-likely to have a positive impact on long-term disability progression, the outcome measure that is the most important to MSers."

Half of all patients with multiple sclerosis (MS) experience cognitive impairment, for which there is no pharmacological treatment. Using magnetic resonance spectroscopy (MRS), we examined metabolic changes in the hippocampi of MS patients, compared the findings to performance on a neurocognitive test battery, and found that N-acetylaspartylglutamate (NAAG) concentration correlated with cognitive functioning. Specifically, MS patients with cognitive impairment had low hippocampal NAAG levels, whereas those with normal cognition demonstrated higher levels. We then evaluated glutamate carboxypeptidase II (GCPII) inhibitors, known to increase brain NAAG levels, on cognition in the experimental autoimmune encephalomyelitis (EAE) model of MS. Whereas GCPII inhibitor administration did not affect physical disabilities, it increased brain NAAG levels and dramatically improved learning and memory test performance compared with vehicle-treated EAE mice. These data suggest that NAAG is a unique biomarker for cognitive function in MS and that inhibition of GCPII might be a unique therapeutic strategy for recovery of cognitive function.

The conclusions say it all, The picture above is not a table but a Barnes Maze where an animal learns where the hidden box is located. The drug was given to mice with MS like disease and they were better at learning where the hidden box was. This was given all the time during the experiment and showed not be that it improved learning but that it stopped the loss of learning ability. It would have been better if they had let the animals acquire a deficit and then seen if there was improvement as this is more applicable to how it would be used in MSers. Interestingly it has been suggestive that this class of drug, i.e. GCPII inhibitor can inhibit excitotoxic glutamate and thus have the potential to induce neuroprotection, which was not seen in the EAE mice, but has been seen in other neurodegenerative models, possibly via activity on metabotrophic glutamate receptors. Symptomatic trials are much shorter than trials for progressive disease, so a symptomatic agent which has other beneficial effects was some advantage as it should be quicker to get to MSers. However this logic failed with cannabinoids as people do not seem to have good access to them

Epub: Skjerbæk et al. Heat sensitive persons with multiple sclerosis are more tolerant to resistance exercise than to endurance exercise. Mult Scler. 2012 Nov.BACKGROUND: Heat sensitivity is reported by 58% of all MSers, causing symptom exacerbation possibly limiting exercise participation.OBJECTIVE: The purpose of this study was to test the hypotheses that (a) a relationship between exercise-induced changes in core-temperature and changes in symptom intensity exists, and (b) that resistance exercise, as a consequence of a minor increase in core temperature, will induce a lesser worsening of symptoms than endurance exercise in heat sensitive MSers.METHODS: On two separate days, 16 heat sensitive MSers randomly completed a session of resistance exercise and endurance exercise or endurance exercise and resistance exercise respectively. Testing was conducted pre, post and one hour after exercise and consisted of Visual Analogue Scale (VAS) scoring (fatigue, spasticity, pain, strength, walking and balance), the 5-time sit-to-stand (5STS), the Multiple Sclerosis Functional Composite (MSFC) and Body Sway. Composite scores describing average subjective symptom intensity and total number of symptoms were calculated from VAS scores.RESULTS: Core-temperature (0.9±0.4°C vs 0.3±0.1°C, p<0.001), subjective symptom intensity 1.7±1.9 cm vs 0.6±1.5 cm, p<0.05) and total number of symptoms (1.6±1.9 vs 0.6±2.1, p<0.05) increased significantly more during endurance exercise than resistance exercise. Changes in core-temperature correlated to changes in symptom intensity (r=0.50, p<0.01). No differences were observed in 5STS, MSFC and Body Sway scores after endurance exercise when compared to resistance exercise.CONCLUSION: An exercise-induced increase in core-temperature is associated with increased number and severity of perceived symptoms in heat sensitive MSers. Based on these findings it is expected that heat sensitive MSers do tolerate resistance exercise better than endurance exercise.

"This study demonstrates how sensitive some MSers are to changes in temperature. Are you? An important question that needs answering in relation to this problem is does these transient changes in temperature-induced changes in neurological function damage and speed up neurodegeneration in the affected pathways. Previous work on the hot-bath tests suggest it may. This clearly needs to be established so that we can advise MSers on what the best course of action to take in relation to exercise and heat."The other post of interest: Multiple Sclerosis Research: Hot bath test; 11 Jun 2012Poll of the week:

OBJECTIVE: The impact of present disease-modifying treatments (DMTs) in multiple sclerosis (MS) on nerve injury and reactive astrogliosis is still unclear. Therefore, we studied the effect of natalizumab treatment on the release of 2 brain-specific tissue damage markers into cerebrospinal fluid (CSF) in MS patients.

METHODS: CSF samples from 92 patients with relapsing forms of MS were collected in a prospective manner prior to natalizumab treatment and after 6 or 12 months. In 86 cases, natalizumab was used as second-line DMT due to breakthrough of disease activity. The levels of neurofilament light (NFL) and glial fibrillary acidic protein (GFAP) were determined using highly sensitive in-house developed enzyme-linked immunosorbent assays.

RESULTS: Natalizumab treatment led to a 3-fold reduction of NFL levels, from a mean value of 1,300 (standard deviation [SD], 2,200) to 400 (SD, 270) ng/l (p < 0.001). The later value was not significantly different from that found in healthy control subjects (350 ng/l; SD, 170; n = 28). Subgroup analysis revealed a consistent effect on NFL release, regardless of previous DMT or whether patients had relapses or were in remission within 3 months prior to natalizumab treatment. No differences between pre- and post-treatment levels of GFAP were detected.

Reducing the immune attack with tysabri, blocks the accumulation of a damaging immune response within the CNS, so nerves do not get damaged and break down Therefore less neurofilament light, a structural molecule of nerves, gets in the CSF. So before treatment there is the amount in the red box after treatment we are in the green which is within normal levels (far right).Therefore blocking relapses is clearly a good thing.

Sunday, 25 November 2012

BACKGROUND: Poor sleep is a frequent symptom in patients with multiple sclerosis (MS). Sleep may be influenced by MS-related symptoms and adverse effects from immunotherapy and symptomatic medications. We aimed to study the prevalence of poor sleep and the influence of socio-demographic and clinical factors on sleep quality in MS- patients.

METHODS: A total of 90 MS patients and 108 sex-and age- matched controls were included in a questionnaire survey. Sleep complaints were evaluated by Pittsburgh Sleep Quality Index (PSQI) and a global PSQI score was used to separate good sleepers (≤5) from poor sleepers (>5). Excessive daytime sleepiness, the use of immunotherapy and antidepressant drugs, symptoms of pain, depression, fatigue and MS-specific health related quality of life were registered. Results were compared between patients and controls and between good and poor sleepers among MS patients.

PURPOSE: To quantify changes in the retinal nerve fiber layer (RNFL) of patients with multiple sclerosis (MS) over 3 years and to evaluate whether treatment protects against RNFL degeneration. METHODS: Ninety-four MS patients and 50 healthy subjects were followed-up over 3 years. All subjects underwent a complete ophthalmic examination, which included assessment of visual acuity (Snellen chart), color vision (Ishihara pseudoisochromatic plates), visual field examination, optical coherence tomography (OCT), and visual evoked potentials (VEP. Shine a light in the eye and measure the brain electrical activity in the brain). All patients were re-evaluated at 12, 24, and 36 months to quantify changes in the RNFL.

RESULTS: Changes were detected in RNFL thickness at the 36-month follow-up. Significant decreases (P<0.05, t test) were observed in the mean, superior (top), inferior (bottom), temporal (Outside) RNFL thicknesses, and macular volume (bit where vision is focused) provided by OCT, and in the P100 latency of VEP (Speed of nerve impulse) of the MS group; but only in the mean and inferior (inside)RNFL thickness of the healthy control group. Greater changes in the superior and inferior RNFL thickness during follow-up were detected in the MS group. Differences between treatments were not detected, but untreated patients had higher degeneration in the mean and superior RNFL thickness during the follow-up (p= 0.040 and p=0.19, respectively). CONCLUSIONS: Progressive axonal loss can be detected in the optic nerve fiber layer of MS patients. Analysis of the RNFL by OCT can be useful for evaluating MS progression and efficacy of treatment as a neuroprotective factor against axonal degeneration.

IshiharaPlate

Schnellen Chart

We have previously posted on what OCT is and how it can detect retinal degeneration. There are changes in the nerve fibres in the eye irrespective of whether you have had optic neuritis. Often it is reflective of more brain activity of lesions. The treatment effect or lack of it showed a tendency for benefit but as it was not signficant we say showed no benefit. However, the interferons have not been reported to inhibit non-relapsing progression. This is another tool at the disposal of the neuro, but if there is a small change seem over 3 years, would this give advantage over looking for a clinical outcome if it takes so long?

PML Risk Infographic

Holistic Management of MS ver. 7.0

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